Spinal cord injury (SCI) often damages, not only white matter axon tracts that transmits signals to and from the brain, but also the central gray matter, causing segmental loss of interneurons and motor neurons. Transplantation of neural stem cells (NSCs) has the potential to replace lost neurons and glia. These transplanted neurons can form functional relays between spinal segments disconnected by the injury. We have generated human NSCs with a spinal cord identity to test the hypothesis that spinal cord NSCs will more appropriately integrate into sites of the injured spinal cord. Our preliminary data provide evidence that both rat and human neural stem cells can be transplanted into multiple models of SCI, including a clinically relevant contusion model. However, humans NSCs appear to develop on a longer timeline, more similar to human development. Therefore, we aim to characterize the maturation and phenotype of human spinal cord NSCs (scNSCs). Long-term studies will assess the efficacy, safety and synaptic integration of such scNSC therapy in a clinically relevant contusive model of cervical SCI. This work is highly innovative and clinically oriented: 1) We will utilize a contusion type injury that is most applicable to human SCI. 2) We will examine a novel human NSC line with a spinal cord identity (scNSCs). 3) Long-term studies will examine the maturation, efficacy and safety of scNSCs, our lead cell candidate, for the treatment of spinal cord injury. 4) Novel trans-synaptic tracing techniques will be used to assess the synaptic integration of both host inputs to the graft and graft outputs to host motor neurons.